Differential impact of <i>TP53</i> and <i>KRAS</i> pathogenic variants on overall survival in advanced ovarian carcinoma.

5583 Background: Advanced epithelial ovarian carcinoma, including high grade serous ovarian carcinoma (HGSOC), clear cell ovarian carcinoma (CCOC), endometrioid ovarian carcinoma (EOC) and mucinous ovarian carcinoma (MOC), frequently presents in advanced stages and is associated with poor outcomes. In addition to common germline mutations in BRCA1/2 , many patients also harbor TP53 and KRAS pathogenic variants (PVs) in their tumors. However, the role of these genomic alterations in advanced epithelial ovarian cancer remains unclear. Methods: Our study examined a large cohort of patients (n = 1060) with advanced epithelial ovarian cancer with genomic profiling performed using next-generation sequencing (StrataNGS). Cox regression modeling was used to examine the associations between TP53 and KRAS PVs and overall survival (OS), adjusting for covariates including age, race/ethnicity, performance status, Charlson Comorbidity Index, and other genomic alterations. Results: Our cohort included HGSOC (n = 924), CCOC (n = 66), EOC (n = 42), and MOC (n = 28). Median OS was 33.4, 33.8, 25.1 and 66.8 months for HGSOC, CCOC, MOC and EOC, respectively. In the CCOC group, TP53 PVs were associated with worse OS (hazard ratio [HR] = 3.23, [95% confidence interval [CI], 1.05-9.89]), while KRAS PVs were associated with better OS (HR = 0.29, [95% CI ,0.09-0.89]). In patients with HGSOC 71.3% had TP53 PVs, whereas 8.0% had KRAS PVs. KRAS PVs were associated with better OS (HR = 0.72, [95% CI, 0.50-1.02]) in HGSOC. TP53 PVs were associated with worse OS only within the sub-cohort that also harbored KRAS PVs (HR = 3.42, [95% CI, 1.13-10.33]. TP53 PVs were not associated with OS in the KRAS wild-type sub-cohort (HR = 0.95, [95% CI, 0.72-1.25]). Our finding that TP53 PVs were associated with worse OS in KRAS PVs sub-cohort was confirmed by interaction analysis (HR = 2.06, [95% CI, 0.98-4.35]). There was no OS difference between TP53 gain-of-function versus non-gain-of-function PVs in HGSOC patients. Conclusions: In our large study cohort of patients with advanced epithelial ovarian carcinoma, we found that TP53 and KRAS PVs were differentially associated with OS. Surprisingly, KRAS PVs were associated with higher OS in HGSOC while TP53 PVs were associated with worse OS only in conjunction with KRAS PVs, highlighting the need to deepen our understanding of the oncogenic role KRAS plays in ovarian epithelial carcinoma. Further mechanistic studies to understand the roles of these common mutations in ovarian cancers could provide deeper insights.